Thyroid Stimulating Hormone Autoantibodies Are Sensitive Biomarkers of Graves’ Disease

Thyroid testing tubeSerum thyroid stimulating hormone autoantibodies (TSAbs) levels are sensitive and specific biomarkers for the diagnosis of Graves’ disease in childhood, and reflect disease severity and activity, according to findings from a large cross-sectional, retrospective study published in the Journal of Clinical Endocrinology and Metabolism.

“This large multicenter study encompassing seven American and European academic tertiary referral centers clearly demonstrates the clinical relevance and clinical utility of this sensitive and specific tool for the early and accurate diagnosis of the complex autoimmune thyroid disease,” said lead author George J. Kahaly, MD, PhD, Professor of Medicine and Endocrinology/Metabolism, Johannes Gutenberg University Medical Center, Mainz, Germany. “The measurement of these specific thyroid autoantibodies both rapidly differentiates between the various causes of the thyroid dysfunction as well as accurately quantifies the clinical severity and activity of this challenging disease,” Dr. Kahaly said.

The researchers analyzed 422 serum samples from 157 children with GD as well as serum samples from 101 control individuals with other thyroid and nonthyroid autoimmune diseases (ie, Hashimoto’s thyroiditis, nonautoimmune hyperthyroidism, type 1 diabetes, and juvenile arthritis), and from 50 healthy children. The researchers compared the sensitivity and specificity of TSAbs to TBII.

In 82 children with Graves’ disease who had not previously been treated, TSAb levels were 100% sensitive and specific, and had 100% positive and negative predictive values. In comparison, corresponding measures for the more widely used TBII assessment were 92.68% (P=0.031), 100%, 100%, and 96.15%, respectively, suggesting that TSAb levels had a significantly higher sensitivity than TBII levels.

A significantly greater percentage of children with Graves’ disease were TSAb positive than TBII positive (94% vs 87.9%; P<0.039), as were a greater percentage of the 263 samples from the children with Graves’ disease (94% vs 89%; P<0.0075). In contrast, all control children and children with other thyroid and nonthyroid autoimmune diseases were TSAb and TBII negative, suggesting that TSAb assessment is “an adequate test for differentiating these disorders from Graves’ disease,” commented Sally Radovick, MD, Lawson Wilkins Professor of Pediatrics and Director of the Division of Pediatric Endocrinology, The Johns Hopkins University School of Medicine, Baltimore, MD. “This is important in that it is rapid, cost effective, and avoids the use of a radionucleotide scan to differentiate the conditions,” she noted.

TSAb levels—but not TBII levels—were significantly higher among children with Graves’ disease and orbital disease compared with those without orbital disease (P<0.001). TSAb also was a marker of severity of orbital disease, while TBII was not. The findings suggest “a possible causal role of TSAb in the pathogenesis and in the development of the clinical phenotype of thyroid eye disease,” the authors reported.

After a median of 3 years of treatment, patients with Graves’ disease without orbital disease showed a greater decrease in TSAb levels compared with patients with orbital disease (69% vs 20% decrease; P<0.001).

“Limitations of this study are its retrospective design, which was recognized by the authors,” Dr. Radovick said. “However, the number of patients and its multicenter design more than compensate for this limitation,” she added.

Background on Thyroid Stimulating Hormone Autoantibody Testing
“Antibodies that cause Graves’ disease are directed at the TSH receptor (TSHR) and can either stimulate, inhibit, or have no effect on receptor function. TSAbs, which are stimulatory auto-antibodies directed against the TSHR, are pathogenic, causing an increase in thyroid follicular cell growth and increased vascularity,” commented Dr. Radovick. “Multiple assays to measure TSAbs have been developed; however, their utility is questioned due to the number antibodies (and their nomenclature) directed at the TSHR, a lack of standardization and reliability of the methods, and the availability of the tests.  Hence, many clinicians do not routinely obtain TSAbs but instead order TSH binding-inhibitory antibodies (TBIIs), which are measured in more standardized assays,” Dr. Radovick said.

“Despite these shortfalls, the presence of TSHR auto-antibodies identify patients at increased risk of GD relapse,” Dr. Radovick continued. “However, the opposite is not true; normal values do not predict patients who will remain in remission. It is nevertheless recommended that antibodies be measured when considering stopping anti-thyroid medication, and if elevated, it is advised that patients be closely followed since it is likely that definitive therapy will be required. In patients with low levels of serum antibodies, anti-thyroid drugs may be stopped, assuming the family is counseled on the signs and symptoms that may suggest relapse,” she said.

“This manuscript goes further to suggest that TSAbs may be useful in the initial diagnosis of GD in children,” Dr. Radovick explained. “The authors compare the use of an automated third generation TBII assay to a sensitive and specific TSAb bioassay, which unlike previous bioassays, now has a shortened turn-around time of 24 hours and greater sensitivity. Furthermore, since the TSAb is a functional assay, it can distinguish between stimulatory and inhibitory immunoglobulins,” she said.

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